In recent years, drug-eluting implantable medical devices, such as, for example, stents, stent grafts, anastomosis devices, vascular grafts, vascular patches, AV shunts, catheters, guide wires, balloons, and filters, have gained more and more acceptance in the medical device industry as an effective means for controlled and sustained local drug delivery. Various drug-eluting coating materials can be applied to the surface of traditional implantable medical devices to impart desired pharmacological effects to the otherwise inert devices, in addition to the basic, mechanical functions performed by the traditional, uncoated devices.
Typically, the drug-eluting coatings comprise one or more biocompatible polymers with the desired pharmacologically active agents encapsulated therein. After implantation of such drug-eluting implantable medical devices, the desired pharmacologically active agents (such as, for example, anti-inflammatory and anti-neoplastic agents) are slowly released from the device surfaces into the local environment in a sustained and controlled manner. Such local drug delivery achieved by the drug-eluting implantable medical devices does not result in any significant increase of the overall drug concentration in the body, thereby substantially reducing the potential toxic effects of the drugs commonly associated with systematic administrations (e.g., intravenous, oral or parenteral administrations). Further, the highly localized concentration and prolonged tissue retention of the desired pharmacologically active agents, as achieved by the implanted medical devices, ensure effective treatment of the target diseased site.
However, the drug release profiles of the implantable medical devices, which are defined by the released drug concentrations plotted as a function of time, are typically limited by the physical and chemical properties of the coating materials used, the thickness of the coatings, and the drug concentration in the coatings. Most of the currently available drug-eluting implantable medical devices have sub-optimal drug release profiles. Some of these devices have either too fast a drug release profile, dumping 70% of the drug load within the first day of implantation, or too slow a drug release profile, releasing only about 10% of the drug load after the first half year of implantation. These design flaws significantly undermine the efficacy of such drug-eluting devices.
Moreover, many of the diseases to be treated by the implantable medical devices are multi-faceted, which require the consorted actions of more than one therapeutic agent to achieve optimal and long-standing efficacy. For instance, restenosis, which is the re-narrowing of an artherosclerotic coronary artery after angioplasty or implantation of a bare metal stent, is caused by a cascade of pathological events following the surgery or stent implantation. It is therefore desirable to include a multitude of therapeutic agents in the coatings of the implantable medical devices for treatment of different aspects of restenosis at different stages. Further, it is desirable to include additional therapeutic agents for treatment of certain sub-populations of patients who do not respond favorably to the main therapeutic agent contained in the coatings.
Unfortunately, very few currently available drug-eluting implantable medical devices are specifically designed and configured for delivery of more than one therapeutic agent, much less optimal delivery of multiple therapeutic agents in a time-differentiated manner for treatment of different aspects of a disease at different stages.
Therefore, there is a need for improved drug-eluting articles that have precisely controlled drug release profiles for optimal delivery of one or more therapeutic agents. There is also a need for improved drug-eluting articles that can provide time-differentiated delivery of multiple therapeutic agents, for treatment of different aspects of a disease at different stages.